Enteric coatings have long been used to inhibit release of drug from tablets and pellets. The enteric coatings are resistant to stomach acid for required periods of time depending on the composition and/or thickness thereof, before they begin to disintegrate and allow for slow release of drug in the stomach and/or upper intestines. Some examples of coatings previously employed are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac as well as shellac and stearic acid (U.S. Pat. No . 2,809,918); polyvinylacetate and ethyl cellulose (U.S. Pat. No. 3,835,221); and neutral copolymer of polymethacrylic acid esters (Eudragit L30D). (F. W. Goodhart et al, Pharm. Tech., pp 64-71, April, 1984); copolymers of methacrylic acid and methacrylic acid methyl ester (Eudragits), or a neutral copolymer of polymethacrylic acid esters containing metallic stearates (Mehta et al U.S. Pat. Nos. 4,728,512 and 4,794,001).
Most available enteric coating polymers begin to become soluble at pH 5.5 and above, with maximum solubility rates at pH's greater than 6.5.
Hydroxypropylmethyl cellulose phthalate (HPMCP) is available from Shin-Etsu Chemical Co., Ltd. who recommend application of this polymer, for use in enteric coatings, in its natural acidic form from organic solvents. This material starts its dissolution process at pH 5.0.
Stafford, J. W., Drug Dev. Ind. Pharm., 8(4), 513-530 (1982) and Bloor, J. R. et al, Drug Dev. Ind. Pharm., 15(14-16), 2227-2243 (1989) describe the use of HPMCP as its totally neutralized form (treated with sodium hydroxide) as an enteric coating applied from aqueous systems. Aqueous systems are preferred due to environmental concerns and flammability/explosion concerns with solvents.
U.S. Pat. No. 4,017,647 and British Patent Specification 1,483,423 discloses HPMCP dissolved in water by neutralizing with a base and applied to tablets or granules by a spray coating technique. However, the coatings are not enteric until they undergo a subsequent acid treatment.
U.K. Patent Application GB 2,057,876A discloses use of HPMCP as its totally neutralized form (treated with sodium hydroxide or ammonium hydroxide) as an enteric coating applied from aqueous systems which coating remains intact for at least 1 hour in contact with HCl of pH 1.2 at 36.degree. to 38.degree. C. and disintegrates within 60 minutes when the pH is raised to 6.8, for example, in a KH.sub.2 PO.sub.4 buffered solution.
Unfortunately, where it has been attempted to coat pellets using a film coating formulation designed for coating tablets, but including a totally neutralized form of HPMCP, as described in the above references, it has been found that unsatisfactory processing results are obtained due to mass differences between tablets and pellets. The tablet film coating formulation causes significant adherence and clumping of the pellets.
Pharmaceutical compositions which include a medicament which is unstable in an acidic environment such as the stomach will require an enteric protective coating to prevent release of such medicament prior to reaching the intestines.
Pravastatin, an HMG CoA reductase inhibitor disclosed in Terahara et al U.S. Pat. No. 4,346,227 and having the formula ##STR1## is sensitive to a low pH environment and will degrade in the stomach.